One-fifth of COVID-19 patients taking nirmatrelvir-ritonavir had viral rebound

A small observational study of ambulatory patients with COVID-19 found that 1.8% of untreated patients tested positive again after testing negative, compared to 20.8% of those who took five days of nirmatrelvir-ritonavir.

Nirmatrelvir-ritonavir was associated with a significantly increased risk of viral rebound compared to no treatment, an observational study found.

The cohort study included 127 ambulatory patients seen for COVID-19 at a health care system in Boston in March 2022 to May 2023. Seventy-two of the patients took five days of nirmatrelvir-ritonavir (Paxlovid) within five days of testing positive, while 55 received no treatment. All participants tested themselves with nasal swabs approximately three times a week for two weeks and weekly thereafter until SARS-CoV-2 was persistently undetectable. The study's primary outcome was viral rebound, defined as either a positive SARS-CoV-2 viral culture after a prior negative result or two consecutive tests with elevated viral loads after a lower viral load result. Results were published by Annals of Internal Medicine on Nov. 14.

Patients in the nirmatrelvir-ritonavir group were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen patients who took the drug had rebound, compared to only one in the untreated group (20.8% vs. 1.8%; absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0]; P=0.001). All of the rebound cases involved a positive result after a negative result. Nirmatrelvir-ritonavir was the only risk factor for rebound identified by multivariable modeling (adjusted odds ratio, 10.02 [95% CI, 1.13 to 88.74]; P=0.038).

Rebound occurred in 26.3% of patients who started therapy within two days of symptom onset and none who started it later. Treated patients with rebound shed virus for a median of 14 days, compared to three days in those without rebound. Half of patients with viral rebound also reported symptom rebound, but the majority of patients reporting symptom rebound did not have viral rebound. Limitations of the study include the differences between treated and untreated patient populations.

“For patients with COVID-19 at low risk for severe disease, the possibility of prolonged shedding should be factored into the consideration of potential risks and benefits of treatment,” said the study authors. They noted that testing five days after completion of therapy might help identify patients with rebound who should stay in isolation, and they recommended that future research look into whether delays in initiation or longer courses of nirmatrelvir-ritonavir could reduce risk of rebound.

An accompanying editorial agreed, particularly with the latter suggestion. “The most compelling explanation for the relationship between [nirmatrelvir-ritonavir] treatment and COVID-19 rebound is that 5 days of treatment at the current dosage is inadequate,” it said. However, the editorial also noted that the current regimen of the drug costs about $1,390 and “therefore, added days of treatment would be very expensive in the absence of a change in the standard treatment plan.”